Hypertension is the leading cause of stroke and cardiovascular diseases, affecting 30% of the adult population. Excessive Na+ input can acutely raise effective circulating volume (ECV) and BP but normally the kidneys excrete enough Na+ and volume to normalize BP, a response termed pressure natriuresis. Thus, hypertension can be considered a failure of pressure natriuresis. In females the response is set to lower arterial pressures than in males and, until menopause, females exhibit lower BP than males. In the previous funding cycle we demonstrated how divergent signals are integrated to impact the overall renal response to hypertensive stimuli in males. We posit that these responses are substantially influenced by sex and present preliminary results demonstrating lower NHE3 and NaPi2, both retracted from proximal microvilli, along with a more rapid natriuretic response to a saline volume expansion in females compared to males. Our overall objectives are to determine how anti-natriuretic stimuli (AngII and L-NAME hypertension) and natriuretic pathways (dopamine, AT2R, GLP1R) are integrated during hypertension at the level of renal transporters and their regulators to balance Na+ output to input, and to use these findings to explain how natriuresis leads to lower pressures in females versus males. We will test the hypothesis that hypertension ensues when natriuretic pathways are inhibited due to blunting of the pressure natriuretic inhibition of transporters in the proximal nephron, and by activation of transporter/channels all along the nephron secondary to intrarenal renin angiotensin system (RSA) activation. We will test the hypothesis that females possess enhanced natriuresis due to lower fractional sodium reabsorption in the proximal nephron as well as reduced intrarenal AngII generation, and that inhibition of specific natriuretic pathways or ovariectomy will eliminate the advantage and identify sex dependent control points. Specific Aim 1 will characterize acute pressure natriuresis in females, then compare male and female responses to two distinct models of experimental hypertension. Mechanisms controlling transporters/channels and their regulators will be determined by assessing mRNA versus protein abundance, subcellular distribution, and intrarenal RAS components. Specific Aim 2 will determine how inhibition of candidate natriuretic pathways alters regulation of transporters/channels during experimental hypertension in females and males: 1) intrarenal dopamine production, 2) AT2 receptor stimulation, and 3) GLP1 receptor stimulation. The effects of negative reciprocity between dopamine and AngII receptors and signaling, well-established in males, will be extended to effects on transporters/channels in both sexes. Significance: Identifying physiologic mechanisms regulating sodium transporters and channels during hypertension that enable females to produce a natriuresis at a lower BP has the potential to advance the field significantly by identifying mechanisms that if enhanced could lower morbidity and mortality in males of all ages, and maintain protection in postmenopausal women.